Hyperglucagonemia is 1) a consistent finding in diabetes mellitus, 2) may contribute to diabetic hyperglycemia and hyperketonemia, and 3) may reflect loss of normal inhibition of glucagon secretion by glucose, insulin, or other factors. The general goal of this proposal is the definition of the mechanisms of normal inhibition of glucagon secretion. Specifically, mechanisms of inhibition of glucagon secretion by glucose, insulin, and fatty acids will be investigated with particular regard to A-cell glucose and energy metabolism. Possible effects of adrenergic agents on A-cell response to glucose, and the postulated feedback between islet cell types will be additional subjects of this study. The proposed experiments will utilize isolated rat islets after maintenance in tissue culture, a procedure which has been shown to restore physiological A-cell function in isolated islets. Glucose and fatty acid metabolism will be determined by production of 3H2O and 14CO2 from the appropriately labeled compounds.